Nitazenes are a chemically defined class of substances derived from the parent compound

nitazene Benzimidazole opioids are a class of synthetic opioids that contain a benzimidazole core structure. The analgesic, pain-relieving properties of these substances were discovered in the mid-1950s by the Swiss company Ciba Specialty Chemicals, Ciba ...

. Nitazenes were developed in the second half of the 1950s by the Swiss Ciba AG as pain-relieving agents. They are important as centrally active, selective

μ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical ...

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

s. The high

potency Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of ho ...

fentanyl Fentanyl is a highly potent synthetic piperidine opioid primarily used as an analgesic (pain medication). It is 30 to 50 times more Potency (pharmacology), potent than heroin and 50 to 100 times more potent than morphine. Its primary Medici ...

(in humans) is matched by only a few nitazenes and surpassed by

etonitazene Etonitazene, also known as EA-4941 or CS-4640, is a List of benzimidazole opioids, benzimidazole opioid, first reported in 1957, that has been shown to have approximately 1,000 to 1,500 times the potency (pharmacology), potency of morphine in anim ...

and

isotonitazene Isotonitazene is a synthetic opioid analgesic drug from the nitazene class and structural homolog of etonitazene, which has been sold as a designer drug. It has only around half the potency of etonitazene in animal studies, but it is likely eve ...

. Due to unacceptable

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s, nitazenes were never included in the pharmacopoeia of human or veterinary medicine. Since 2019, highly potent nitazenes have proliferated as ″new synthetic opioids″ in the North American and European narcotics markets and as such have become a formative component of the

opioid epidemic in the United States There is an ongoing opioid epidemic (also known as the opioid crisis) in the United States, originating out of both medical prescriptions and illegal sources. It has been described as "one of the most devastating public health catastrophes ...

. Overdoses of nitazene opioids have led to several hundred documented fatalities.

History

In the mid-1950s, the pharmaceutical research department of the Ciba AG discovered the (low) analgesic effect of 1-(''β''-diethylaminoethyl)-2-benzylbenzimidazole (desnitazene). Systematic

derivatization Derivatization is a technique used in chemistry which converts a chemical compound into a product (the reaction's derivate) of similar chemical structure, called a derivative. Generally, a specific functional group of the compound participates ...

of this parent compound in the course of structure-activity relationship investigations revealed an enhancement of activity by

nitration In organic chemistry, nitration is a general class of chemical processes for the introduction of a nitro group () into an organic compound. The term also is applied incorrectly to the different process of forming nitrate esters () between Alcohol ...

of the 5-position. 4'-Methoxylated and ethoxylated compounds achieved potencies in the

hot plate test The hot plate test is a test of the pain response in animals, similar to the tail flick test. Both hot plate and tail-flick methods are used generally for centrally acting analgesic, while peripherally acting drugs are ineffective in these tests b ...

that were previously unattained. The thus discovered etonitazene is the most potent nitazene opioid known to date. The

morphine Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies (''Papaver somniferum''). It is mainly used as an analgesic (pain medication). There are ...

-like mechanism of action was elucidated from the antagonizability of analgesia with allylnormorphine. In a human clinical trail two nitazenes (etonitazene and clonitazene) were investigated in 363 patients and the results were published in 1958. The nitazenes were notable for their low

therapeutic index The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug with regard to risk of overdose. It is a comparison of the amount of a therapeutic agent that causes toxicity to the ...

, which precludes their marketability as

pharmaceutical drugs Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the ...

. March 2019 marked the beginning of the spread of nitazene opioids in the drug scene.

Isotonitazene Isotonitazene is a synthetic opioid analgesic drug from the nitazene class and structural homolog of etonitazene, which has been sold as a designer drug. It has only around half the potency of etonitazene in animal studies, but it is likely eve ...

was the first member of the substance class to be offered for sale on the darknet and forensically detected in overdose deaths in Switzerland and Canada.

Structure

Nitazenes are

benzimidazole Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound may be viewed as fused rings of the aromatic compounds benzene and imidazole. It is a white solid that appears in form of tabular crystals. Preparation Benzimi ...

s that are

substituted Substitution may refer to: Arts and media *Substitution (poetry), a variation in poetic scansion *Substitution (theatre), an acting methodology Music *Chord substitution, swapping one chord for a related one within a chord progression *Tritone ...

with a diethylaminoethyl group at the 1-position, in the 2-position with a

benzyl group In organic chemistry, benzyl is the substituent or molecular fragment possessing the structure . Benzyl features a benzene ring () attached to a methylene group (). Nomenclature In IUPAC nomenclature, the prefix benzyl refers to a substituent, ...

and in the 5-position with a

nitro group In organic chemistry, nitro compounds are organic compounds that contain one or more nitro functional groups (). The nitro group is one of the most common explosophores (functional group that makes a compound explosive) used globally. The nit ...

. Compounds nitrated in the 6-position are less effective, the 4- or 7-nitro

isomer In chemistry, isomers are molecules or polyatomic ions with identical molecular formula – that is, the same number of atoms of each element (chemistry), element – but distinct arrangements of atoms in space. ''Isomerism'' refers to the exi ...

s are not analgesically active. Analgesically active nitazenes are also often substituted in the ''para''-position of the benzyl group, more rarely in the ''meta'' position. At the methylene linker, a

methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula (whereas normal methane has the formula ). In formulas, the group is often abbreviated as ...

or an amide group is tolerated stereospecifically by the target receptor. Nitazenes are structurally unrelated to other opioids.

Analysis

Since 2024, a

immunoassay An immunoassay (IA) is a biochemical test that measures the presence or concentration of a macromolecule or a small molecule in a solution through the use of an antibody (usually) or an antigen (sometimes). The molecule detected by the immunoassay ...

-based point-of-care testing in the form of test strips is available for the detection of nitazenes.BTNX Harm Reduction, Nitazene Test Strip
/ref> The drug sample is added to water and requires sufficient solubility for the test to be successful. The

detection limit The limit of detection (LOD or LoD) is the lowest signal, or the lowest corresponding quantity to be determined (or extracted) from the signal, that can be observed with a sufficient degree of confidence or statistical significance. However, the ...

of the highly potent

is given as 2000-3000 ng/mL. The test is of limited general applicability for non-nitazene

benzimidazole opioids Benzimidazole opioids are a class of synthetic opioids that contain a benzimidazole core structure. The analgesic, pain-relieving properties of these substances were discovered in the mid-1950s by the Swiss company Ciba Specialty Chemicals, Ciba ...

. Desnitazenes, for example, which are not substituted at the benzo structure portion, cannot be successfully tested by this method. According to the manufacturer, there is no

cross-reactivity Cross-reactivity, in a general sense, is the reactivity of an observed agent which initiates reactions outside the main reaction expected. This has implications for any kind of test or assay, including diagnostic tests in medicine, and can be a c ...

with frequently used

adulterant An adulterant is a substance secretly added to another that may compromise the safety or effectiveness. Typical substances that are adulterated include food, cosmetics, pharmaceuticals or fuels. Definition Adulteration is the practice of secre ...

s such as

acetaminophen Paracetamol, or acetaminophen, is a non-opioid analgesic and antipyretic agent used to treat fever and mild to moderate pain. It is a widely available over-the-counter drug sold under various brand names, including Tylenol and Panadol. Parac ...

caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine chemical classification, class and is the most commonly consumed Psychoactive drug, psychoactive substance globally. It is mainly used for its eugeroic (wakefulness pr ...

diphenhydramine Diphenhydramine, sold under the brand name Benadryl among others, is an antihistamine and sedative. Although generally considered sedating, diphenhydramine can cause paradoxical central nervous system stimulation in some individuals, particula ...

, other non-benzimidazole opioids (heroin, methadone, fentanyl) and common non-opioid drugs (

xylazine Xylazine is a structural analog of clonidine and an α2-adrenergic receptor, α2-adrenergic receptor agonist, sold under many trade names worldwide, most notably the Bayer brand name Rompun, as well as Anased, Sedazine and Chanazine. Xylazine ...

MDMA 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy (tablet form), and molly (crystal form), is an empathogen–entactogenic drug with stimulant and minor Psychedelic drug, psychedelic properties. In studies, it has been used ...

cocaine Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...

ketamine Ketamine is a cyclohexanone-derived general anesthetic and NMDA receptor antagonist with analgesic and hallucinogenic properties, used medically for anesthesia, depression, and pain management. Ketamine exists as its S- (esketamine) a ...

Pharmacology

Metabolism

The metabolization of nitazenes is species-dependent. In humans, the main degradation pathways are ''N''-deethylation and, in cases of 4'-ethers, ''O''-dealkylation. The 4'-hydroxy compounds are eliminated more quickly via the

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

due to higher

hydrophilicity A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are no ...

and are predominantly detectable in the urine.

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

CYP2C8 Cytochrome P4502C8 (CYP2C8) is a member of the cytochrome P450 mixed-function oxidase system involved in the metabolism of xenobiotics in the body. Cytochrome P4502C8 also possesses epoxygenase activity, i.e. it metabolizes long-chain polyunsat ...

are likely to be involved in ''N''-deethylation. Reduction of the nitro group occurs extrahepatically, probably via bacteria of the intestinal flora. Bioconjugates are excreted as various ''O''-

glucuronide A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond. The glucuronides belong to the glycosides. Glucuronidation, the conversion of chemical compounds to glucu ...

s. The ''N3'' oxide is a secondary metabolite in humans. The 4'-hydroxy compounds in urine and the ''N''-deethyl compounds in blood serve as forensic

biomarkers In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...

References

{{Chemical classes of psychoactive drugs Nitazenes